This Harvard discovery could change the human biological clock

A team of scientists published an article in Cell in which he states that he was able reverse the effects of aging in mice. Previously, scientists caused accelerated aging in animals.

Professor of genetics and co-director of the Paul F. Glenn Center for Research in the Biology of Aging at Harvard Medical School, David Sinclair and his team focused on part of the genome called the epigenome, which is responsible for telling each cell what function it has and when it must perform it. This means that a skin cell differentiates into a skin cell and a brain cell into a brain cell at the right time.

The epigenome gives each cell different instructions about which genes to turn on and which to shut off. at every moment. Epigenetics would act as a pattern that a seamstress would use to make a piece of clothing. The fabric to start with would be the same, but the pattern would determine whether the garment would be trousers, a shirt or a jacket. In the case of cells, the instructions given by the epigenome lead to cells with different physical structures and functions in a process known as differentiation.

Scientists have succeeded in reversing the effects of aging they previously caused in mice. This reversibility, they say, supports the hypothesis that the main factors in aging are not DNA mutations, but errors in epigenetic instructions which somehow went awry.

Sinclair has long argued that aging results from the loss of critical instructions that cells need to continue to function. That’s what he calls it Information theory of aging. “The basis of aging is the information that is lost in the cells, not just the accumulation of damage,” he says. “It’s a paradigm shift in how we think about aging.”

Spanish researcher Maria Blasco demonstrated how with aging and telomere shortening in cells, this means that the DNA ends of the chromosomes disappear. This conclusion could be consistent with Sinclair’s finding.

The results of the study seem to support Sinclair. The researcher compares the process to a computer program that works fine, but one day it crashes, and after restarting it, it works fine again. “If the cause of aging is that the cell is filled with mutations, then it would be impossible to reverse age.”, states. “But by showing that we can reverse the aging process, we show that the system is intact, that there is a backup, and that a software reset is necessary.”

The researchers mimicked the effects of aging on the mouse epigenome by introducing breaks into the DNA of young rodents. By doing so, they would mimic the epigenetic changes that can occur naturally in humans, derived from tobacco use, exposure to pollution and chemicals. After they had aged in this way, the mice began to show signs of aging within weeks. Their hair turned gray, they lost weight even on the same diet, they moved less and became frail.

What happened was that the epigenetic instructions led the cells to re-initiate the genetic changes that defined their identity. These genes came from a set of so-called Yamanaka stem cell factorsa set of four genes discovered by scientist Shinya Yamanaka in 2006 that can reset the clocks of adult cells to an embryonic, stem cell state so they can start their development or differentiation process again.

Sinclair didn’t want to completely erase the cells’ epigenetic history, just reset it enough to reset the epigenetic instructions. Using three of the four factors turned back time by 57%, enough to make mice young again.

“We’re not creating stem cells, we’re turning back time for them to regain their identity,” Sinclair explains. “I was very surprised by the universality of how it works. We haven’t yet found a type of cell that we can’t age forwards and backwards.”

But the scientists succeeded in rejuvenating the mice’s cells Will this technique work in humans? This will be another challenge for Sinclair and his team testing subhuman primates. They are currently working on creating a biological switch which allows them to turn the clock on and off by combining the activation of reprogramming genes with an antibiotic called doxycycline. If doxycycline is given to the animals, the clock starts to reverse, and when doxycycline is not given, the process stops. Sinclair is testing the system with human neurons, skin cells and fibroblasts, which make up connective tissue.

In 2020, Sinclair announced that in mice, this process restored sight in old animals. Current results show that the system can be applied not only to a tissue or an organ, but to the entire organism of an animal. The scientist believes that the technique will first be tested in eye diseases, as the therapy can be applied directly to the area.

“We think that the processes that underlie aging and related diseases are irreversible,” says Sinclair. “With the eye, there’s a misconception that you have to grow new nerves. But in some cases, the existing cells just don’t work so if you restart them they are fine. It’s a new way of thinking about medicine.” According to this reasoning, some chronic diseases like heart disease or even degenerative diseases like Alzheimer’s could be treated by reversing the aging process that causes them.

Reference:
Blasco, M. A. (2007). Telomere length, stem cells and aging. Nature chemical biology, 3(10), 640-649.

Yang, JH, Hayano, M. et al. al. 2023. Loss of epigenetic information as a cause of mammalian aging. Cell. DOI: https://doi.org/10.1016/j.cell.2022.12.027